The overall hypothesis of this proposal is that interactions between BDNF/TrkB and GPCR signaling in the striatum are critical to the brain's ability to respond to excessive dopaminergic and glutamatergic neurotransmission caused by amphetamine (AMPH) administration. Along with genes/proteins that mediate the psychomotor response to stimulants, endogenous inhibitory systems that modulate the amplitude and duration of the response are activated. For example, the G-protein-coupled receptors (GPCRs), GABAB, NK-1, mu opioid and delta opioid receptors, as well as the tyrosine kinase receptor, TrkB, activated by brain-derived neurotrophic factor (BDNF), regulate the local striatal network. Further, using cDNA array analyses, we have identified genes coding for intracellular signaling proteins that are up- or downregulated by acute amphetamine. These include the Serum and Glucocorticoid-Regulated Kinase 1 (SGK1) and the Regulator of G-protein Signalling 4 (RGS4). Alteration of these genes and proteins suggests that the striatum responds to an initial, moderate dose of AMPH with a robust repertoire of compensatory mechanisms aimed at bringing the network back to homeostasis. In Aim 1 of this competitve renewal, the contribution of striatal PIS kinase-regulated cascades to acute and repeated AMPH effects will be investigated. Rats will be infused intrastriatally with drugs that inhibit selective aspects of GPCR signaling to investigate whether they contribute to the behavioral and neurochemical responses of the striatum to acute AMPH. Changes in nuclear and cytoplasmic PI3-kinase activity and the phospho-proteins, ERK, Akt/PKB and SGK1 will be evaluated. In Aim 2, the contribution of striatal RGS4 signaling to acute and repeated AMPH effects will be investigated. The subcellular localization of RGS4 and the effects of HSV-RGS4 overexpression on Group I mGluRs and Homer 2 as well as nuclear and cytoplasmic ERK and PI3-kinase regulated phosphoproteins in the striatum will be determined. Further, changes in the association of RGS4 with Group I mGluRs and Homer 2 will be examined after selective mGluR receptor stimulation. In Aim 3, the contribution of striatal BDNF/trkB signaling to acute and repeated AMPH effects will be investigated. Cortical BDNF mRNA and cortical and striatal BDNF and phospho-TrkB protein levels will be examined at different times after AMPH. In addition, rats will be infused intrastriatally with drugs that inhibit TrkB signaling to investigate whether BDNF/TrkB contributes to the changes in striatal PIS kinase-regulated cascades (SGK1 and Akt/PKB) elicited by AMPH. Identifying and enhancing the amplitude and duration of homeostatic mechanisms in the striatum has the potential of targeting novel neuronal signaling systems for medicinal development to treat psychostimulant abuse and to improve public health.